Sacubitril, chemical name being 4-{[(2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl]amino}-4-oxobutanoic acid), is an enkephalinase inhibitor. Its structure is as follows:

Enkephalinase (NEP) is a metalloproteinase expressed in various tissues and is most abundant in the kidney. It can catalyze the degradation of various endogenous peptides, such as NP, bradykinin, substance P, etc. Therefore, the NEP inhibitor can increase the levels of urinary natriuretic peptide (NP). NP, playing an important role in the body fluid balance, has three subtypes, including type A (ANP), type B (BNP) and type C (CNP). When the blood vessel volume overload causes an increase of atrial pressure, the atrium releases ANP, which is also called atrial natriuretic peptide. Increased left ventricular filling pressure can promote BNP release, and ANP and BNP have effects on the vasodilation and the excretion of sodium as well as diuresis. CNP is mainly expressed in the central nervous system, kidney and vascular endothelial cells, and has an antithrombotic effect. Excessive plasma volume and left ventricular filling pressure can stimulate the release of NP, especially in patients with heart failure. Direct vasodilation of NP reduces ventricular preload, systemic vascular resistance, and arterial pressure, and NP can directly exert vasodilation effect by reducing ventricular preload, systemic vascular resistance, and arterial pressure. In addition, NP can also increase the filtration rate of glomeruli, and promote the excretion of sodium as well as water. NP also reduces the release of renin, lowers plasma angiotensin II levels, and relaxes blood vessels.
Angiotensin II (Ang II) is a potent vasoconstrictor and is the most important active hormone in the renin-angiotensin-aldosterone system (RAAS). It plays a major role in the cardiovascular disease and can exert a direct effect on raising blood pressure. There are at least two subtypes of AngII receptors, including AT1 and AT2. AngII is highly selective for the AT1 receptor and shows 300 times greater affinity than for the AT2 receptor. When AngII binds to the AT1 receptor, it activates the corresponding cellular pathway, thereby exhibiting the main effects of AngII such as vasoconstriction, aldosterone secretion, and renal tubular reabsorption of sodium as well as water. AT1 receptor antagonists can inhibit AngII-mediated vasoconstriction, renal tubular reabsorption of sodium as well as water, regulation of RAAS on baroreceptors, and sympathetic excitation. AT1 receptor antagonists have been widely used in the treatment of hypertension.
The combined administration of sacubitril or its salt with an angiotensin II AT1 receptor antagonist, such as valsartan, can simultaneously inhibit enkephalinase and angiotensin receptor, that is, it can simultaneously act on renin-angiotensin system and promote the circulation of brain natriuretic peptides, thereby acting on the neuroendocrine system of the heart in a variety of ways, blocking receptors that exert harmful effects, and promoting protective mechanisms. LCZ-696 (Entresto), developed by Novartis, is a eutectic composed of sacubitril sodium and valsartan disodium, and used for the treatment of chronic heart failure and/or hypertension with remarkable effects and good safety. At present the drug has been submitted for new drug application in the United States, the European Union and other countries, and has been approved by the FDA, which is the first new drug approved for chronic heart failure in the past 10 years.
Novartis developed sacubitril sodium along with valsartan disodium into the eutectic, LCZ-696. One of the reasons is that LCZ-696 is less hygroscopic than sacubitril sodium, which is more advantageous to production and storage. Although the LCZ-696 eutectic has improved in physical properties, the fixed composition ratio limits the use of combination medication of sacubitril with various ratios of valsartan or its pharmaceutically acceptable salt, or other AT1 receptor antagonists, which is not conducive to clinical adjustment according to different conditions. The free acid of sacubitril is not suitable for the formulation, especially oral solid dosage forms, because of its low melting point and poor water solubility. The amorphous form of the sacubitril sodium salt is highly hygroscopic and difficult to prepare. U.S. Pat. No. 5,217,996 discloses a solid form of sacubitril sodium salt X, which is prepared according to the method thereof, and is found to have a great hygroscopicity. Therefore, it needs to further study the solid form of sacubitril sodium salt in order to obtain the sacubitril sodium salt with simple preparation process and improved physical properties such as hygroscopicity.
It has been demonstrated that it is very difficult to form a sacubitril sodium salt having the desired advantageous properties, and in most cases, the obtained sodium salt forms are poor in stability. This study shows that the crystalline forms of the sacubitril salt in the present invention are particularly advantageous.